1. Field of the Invention
The present invention is in the fields of pharmaceuticals, formulations chemistry and pharmacology. The invention generally relates to compositions comprising carisoprodol or pharmaceutically acceptable salts, esters or derivatives thereof. In certain embodiments, the invention provides pharmaceutical compositions comprising the skeletal muscle relaxant carisoprodol and one or more additional active agents selected from the group consisting of at least one non-aspirin non-steroidal antiinflammatory drug (non-aspirin NSAID), one or more muscle relaxing compounds, one or more anxiolytic compounds, one or more narcotic analgesics, one or more non-narcotic analgesics, one or more anticonvulsants, one or more antipsychotics, and one or more antidepressants. In additional embodiments, the invention provides methods of use of such compositions in preventing, alleviating and/or treating musculoskeletal pain, muscle spasms, or other non-malignant painful conditions, including methods in which the circulating levels of the active pharmaceutical form of carisoprodol are controlled by the use of suitable drug delivery systems like immediate release tablets, extended, modified or controlled-release tablets, topicals, transdermals and/or by strict control of dosage regimen. In some embodiments, the invention provides a reduced level of somnolence while maintaining therapeutic efficacy using appropriate amount of drug or reduced frequency of dosing.
2. Related Art
Carisoprodol is a skeletal muscle relaxant. It is indicated as an adjunctive to rest, physical therapy, and other measures for the relief of discomfort associated with acute, painful musculoskeletal conditions. Carisoprodol has the following structure:
The chemical name for carisoprodol is N-isopropyl-2-methyl-2-propyl-1,3-propanediol dicarbamate, and its molecular formula is C12H24N2O4.
Carisoprodol is a centrally acting skeletal muscle relaxant that does not directly relax tense skeletal muscles in man. The mode of action of carisoprodol in relieving acute muscle spasm of local origin has not been clearly identified, but may be related to its sedative properties. In animals, carisoprodol has been shown to produce muscle relaxation by blocking interneuronal activity and depressing transmission of polysynaptic neurons in the spinal cord and in the descending reticular formation of the brain. The onset of action is rapid and lasts four to six hours.
Carisoprodol is metabolized in the liver and is excreted by the kidneys. One of the products of metabolism, meprobamate, is active as an anxiolytic. The degree to which it contributes to the efficacy of carisoprodol is unknown.
Carisoprodol is available in 250 mg and 350 mg immediate release tablets (SOMA®, Meda Pharmaceuticals Inc., Somerset, N.J.), in tablets containing a combination of 200 mg carisoprodol and 325 mg aspirin (SOMA® Compound, Meda Pharmaceuticals Inc., Somerset, N.J.) and in tablets containing a combination of 200 mg carisoprodol, 325 mg aspirin and 16 mg codeine phosphate (SOMA® Compound with Codeine CIII, Meda Pharmaceuticals Inc., Somerset, N.J.).
U.S. Pat. Nos. 4,923,898, 4,722,938 and 4,780,463 disclose pharmaceutical analgesic, anti-inflammatory and skeletal muscle relaxant compositions and methods of using same comprising an analgesically and anti-inflammatory effective amount of at least one non-steroidal anti-inflammatory drug other than aspirin, acetaminophen and phenacetin, in combination with an effective amount of a skeletal muscle relaxant.
U.S. Pat. No. 5,260,337 discloses pharmaceutical compositions for use in the treatment of pain and inflammation and the treatment of muscle spasms and associated pain, soreness and tightness of muscles in mammalian organism, the composition comprising: (i) an analgesically and anti-inflammatory effective amount of (S)-ibuprofen, or a salt thereof, substantially free of (R)-ibuprofen; and (ii) an amount effective in the treatment of muscle spasms of at least one of the muscle relaxants, or a therapeutically active stereoisomer thereof, substantially free of its other stereoisomers.
Non-steroidal anti-inflammatory drugs (NSAIDs) are drugs that reduce pain, fever and inflammation. They are used for the treatment of acute or chronic conditions where pain and inflammation are present. NSAIDs are classified as non-selective inhibitors of the enzyme cyclooxygenase, as selective cyclooxygenase-1 (COX-1) inhibitors and selective cyclooxygenase-2 (COX-2) inhibitors. NSAIDs can also be classified based on their chemical structure, including, but not limited to, acetic acid derivatives such as diclofenac, aceclofenac, ketorolac, and propionic acid derivatives such as ibuprofen, flurbiprofen, ketoprofen and naproxen.
Various muscle relaxing compounds other than carisoprodol exist. The skeletal muscle relaxants may act locally on the skeletal muscle or centrally on the central nervous system (CNS). These muscle relaxing compounds may possess mild depressant properties on the CNS. Typical examples of such muscle relaxing compounds include, but are not limited to, mephenesin (MYANESIN®, TOLSEROL®), mephenesin carbamate (TOLSERAM®), mephenesin acid succinate, methocarbamol (DELASIN®, FORBAXIN®), chlorphenesin carbamate (MAOLATE®), mephenoxalone, metaxalone (SKELAXIN®), meprobamate (AMOSENE®, BAMATE®, EQUAGESIC®, EQUANIL®, MEPRIAM®, MEPRO-ASPIRIN®, MICRAININ®, MILPREM-200®, MILPREM-400®, MILTOWN®, NEURAMATE®, PMB 200®, PMB 400®, Q-GESIC®, and TRANMEP®), zoxazolamine (FLEXIN®), chlorzoxazone (PARAFLEX®, PARAFON FORTE DSC®, STRIFON FORTE DSC®), chlordiazepoxide HCl (A-POXIDE®, CHLORDIAZACHEL®, LIBRIUM®, LYGEN®); diazepam (VALIUM®), analexin, baclofen (KEMSTRO®, LIORESAL®), chlormezanone (TRANCOPAL®), cyclobenzaprine HCl (FLEXERIL®), orphenadrine citrate (INVAGESIC®, INVAGESIC FORTE®, NORFLEX®, NORGESIC®, NORGESIC FORTE®, ORPHENGESIC®, ORPHENGESIC FORTE®), alcuronium, atracurium, cisatracurium, dimethyltubocurarine, doxacurium chloride, fazadinium bromide, gallamine, hexafluoronium, mivacurium chloride, pancuronium, pipecuronium bromide, rocuronium bromide, suxamethonium, tubocurarine, vecuronium, febarbamate, phenprobamate, phenyramidol, pridinol, styramate, tetrazepam, thiocolchicoside, tizanidine, tolperisone, and dantrolene.
NAXADOL® (Syntex, S.A. of C.V., Mexico) is a muscle relaxant in the form of capsules containing 250 mg naproxen and 200 mg carisoprodol. It is indicated for the alleviation of musculoskeletal pain.
DOLAREN® (Laboratorios A.F., S.A. of C.V., Mexico) is also indicated for the treatment of musculoskeletal pain and contains 50 mg of diclofenac and 200 mg of carisoprodol.
There exists a need for pharmaceutical compositions containing carisoprodol and one or more additional active agents and treatment methods that relieve musculoskeletal pain with reduced side effects, such as somnolence, and that provide a rapid onset of pain relief. There also exists a need for pharmaceutical compositions that provide a controlled release of carisoprodol, with or without one or more additional active agents, for convenient dosing and more effective treatment of musculoskeletal pain. There also exists a need for pharmaceutical compositions containing carisoprodol with or without one or more additional active agents and treatment methods for topical or transdermal application that relieve musculoskeletal pain with reduced side effects, such as somnolence and that also provide a more effective treatment of musculoskeletal pain.